Inactivation of the Hippo pathway followed by the nuclear accumulation of the transcriptional co-activator yes-associated protein (YAP) induces liver tumour formation through the induction of genomic instability and cell proliferation. Increased YAP activity defines HCC patients with poor prognosis and early tumour recurrence. The YAP paralog TAZ (WWTR1) is also regulated by the Hippo pathway. Its oncogenic properties have been demonstrated for breast cancer and very recent work illustrates that TAZ promotes liver fibrosis. Whether YAP and TAZ are regulated by identical cellular features and if they facilitate their biological functions via exclusive or partly identical effector mechanisms in different stages of liver tumourdevelopment is not understood. In three work packages (WPs), we will systematically analyse different levels of YAP and TAZ biology in hepatocarcinogenesis. By using a siRNA screen and proteomics, the common and/or exclusive mechanisms of YAP and/or TAZ regulation and activity will be identified (WP1). To decipher their exclusive and common biological features, we will define target genes regulated by YAP and TAZ alone or in combination by transcriptome expression profiling. The biological relevance of these target genes will be confirmed in vivo by hydrodynamic gene delivery (WP2). In vivo, we will examine if the loss of YAP and/or TAZ affects hepatocyte biology and the cross-talk with other liver cell types under regenerative conditions and during chronic liver damage. Finally, we will analyse if YAP and/or TAZ deficiency affects the tumourinitiating properties of key oncogenes and signalling pathways in liver tumorigenesis (WP3). This project will unravel how and to which extent YAP and TAZ facilitate common and exclusive oncogenic features in different stages of liver tumorigenesis. The results will affect the design of potential therapeutic approaches in patients, which show a dysregulation of the Hippo/YAP/TAZ signalling pathway.